RESUMO
Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLEâ¯=â¯0.3, ΔFsp3â¯=â¯0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Descoberta de Drogas , Receptores de Superfície Celular/agonistas , Tiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Knockout , Estrutura Molecular , Ratos , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/metabolismo , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
Treatment of various ketones with ethyl dibromofluoroacetate in the presence of diethylzinc and dimethylaminoethanol or triphenylphosphine provides rapid access to corresponding fluorinated glycidic esters. Simplified workup allowed first characterization of these compounds.
Assuntos
Compostos de Epóxi/síntese química , Hidrocarbonetos Fluorados/síntese química , Cetonas/química , Catálise , Química Orgânica/métodos , Compostos de Epóxi/química , Ésteres , Hidrocarbonetos Fluorados/química , Estrutura Molecular , EstereoisomerismoRESUMO
The rhodium-catalyzed 1,4-addition of arylboronic acids to an enantiopure heterocyclic acceptor proceeds under ligand control to effect an asymmetric synthesis of functionalized pyrrolizidinones. The protocol allows convenient access to all four stereoisomers of pyrrolizidinone 3a (Ar = Ph) by appropriate selection of substrate and catalyst.
RESUMO
The enantioselective synthesis of a potent Maxi-K potassium channel opener (BMS-204352) mediated by N-fluoroammonium salts of cinchona alkaloids is described. Two synthetic pathways were evaluated. An ee as high as 88% was achieved (>99% after a single recrystallisation).
